Sustained activation of PGE2 synthesis in mesangial cells cocultured with glomerular endothelial cells

Glomerular endothelial cells synthesize and release endothelin-1 (ET-1), and mesangial cells, normally closely apposed to endothelial cells in vivo, respond to ET-1 with contraction, proliferation, and prostaglandin E2 (PGE2) release. This study sought to determine whether chronic coculture of mesangial cells with glomerular endothelial cells alters mesangial cell PGE2 synthesis. Mesangial cells cocultured with endothelial cells were found to release PGE2 at rates much greater than those observed in mesangial cells not cocultured with endothelial cells. This effect persisted for at least 24 h after the mesangial cells were removed from coculture with endothelial cells. The increase in basal mesangial cell PGE2 synthesis was dependent on endothelial cell-derived ET-1. Despite the increase in basal PGE2 synthesis after coculture with endothelial cells, acute ET-1-stimulated PGE2 release was markedly blunted in mesangial cells that had been cocultured with endothelial cells when compared with mesangial cells in solo-culture. This lack of responsiveness was specific for ET-1 and resulted from a profound downregulation of mesangial cell endothelin receptors. Thus coculture with endothelial cells produces two apparently opposing and ET-1-dependent effects in mesangial cells, namely a sustained increase in basal PGE2 synthesis by the cells and a loss of responsiveness to further stimulation with ET-1. It is postulated that the induction of sustained PGE2 synthesis may also occur in vivo if endothelin release from endothelial cells is stimulated and may explain, in part, the extraordinary sensitivity of some patients with glomerular disease to cyclooxygenase inhibitors.